More than 750,000 people in the United States die from coronary heart disease and strokes every year. About 1.25 million people have heart attacks every year, half of which occur without warning. Coronary heart disease is the most frequent killer of men and women in the United States. Despite a century of drug development, ten times as many Americans die of heart attacks as at the turn of the century.
According to the American Heart Association, cholesterol levels are the major predictors of cardiovascular disease. Cholesterol, a soft, waxy substance found among the lipids in the blood stream, is an important part of a healthy body because it is used to form cell membranes, some hormones and other needed tissues. However, a high level of cholesterol in the blood (hypercholesterolemia) is a major risk factor for coronary heart disease, which leads to heart attack.
Cholesterol is insoluble in the blood, and must be transported to and from the cells by a special carrier of lipids and proteins called lipoproteins. There are several kinds of lipoproteins, the most important of which are low-density lipoprotein (LDL) and high-density lipoprotein (HDL).
Low-density lipoprotein is the major cholesterol carrier in the blood. Excess LDL cholesterol circulating in the blood can slowly build up within the walls of the arteries feeding the heart and brain. Together with other substances it can form plaque, a thick, hard deposit that can clog those arteries. This condition is known as atherosclerosis. The formation of a clot (or thrombus) in the region of this plaque can block the flow of blood to part of the heart muscle and cause a heart attack. If a clot blocks the flow of blood to part of the brain, the result is a stroke. A high level of LDL cholesterol reflects an increased risk of heart disease. Thus, LDL cholesterol is often called "bad cholesterol."
High density lipoprotein ("HDL") carries about one-third to one-fourth of blood cholesterol. It is believed that HDL carries cholesterol away from the arteries and back to the liver, from which it is ultimately passed from the body. Some experts believe HDL removes excess cholesterol from atherosclerotic plaques and thus slows their growth. HDL is known as "good cholesterol" because a high level of HDL seems to protect against heart attack. The opposite is also true: a low HDL level indicates a greater risk.
Cholesterol comes from two sources. It is produced in the body, mostly in the liver (about 1,000 milligrams a day), and is also found in foods that come from animals, such as meat, poultry, fish, seafood and dairy products. Foods from plants (fruits, vegetables, grains, nuts and seeds) do not contain cholesterol.
Saturated fatty acids are the chief culprit in raising blood cholesterol, which increases the risk of heart disease. But dietary cholesterol also plays a part. The average American man consumes about 360 milligrams of cholesterol a day; the average American woman, between 220 and 260 milligrams.
One hundred (100) million adults have blood cholesterol levels of 200 milligrams per deciliter (mg/dl) or higher, and nearly 40 million Americans have levels of 240 mg/dl or above. It is estimated that there are 53 million Americans with LDL levels that require treatment, but that less than one-third of those in need are receiving the necessary treatment. Furthermore, most patients who are treated fail to attain treatment goals. The yearly cost of treatment is estimated at more than $100 billion, yet coronary heart disease still remains the No. 1 killer of Americans.
Thus, the risk of having a heart attack or stroke is strongly predicted by the amounts of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides in the blood.
Cholesterol and triglyceride levels can be reduced through medical intervention and/or dietary modification, such as reduction of the dietary intake of cholesterol and saturated fats. However, some dietary modifications have given rise to new problems. For example, in recent years the substitution of margarine for butter has been promoted. Butter is high in cholesterol and saturated fats. Stick margarine, on the other hand, has a semi-solid consistency based on their content of hydrogenated oils. The hydrogenation process, however, forms trans fats. Clinical studies have demonstrated that trans fats are atherogenic, causing two to three times the cardiovascular risk of the naturally saturated fats which give butter its stability. The health advantage of margarine over butter is now suspect in that margarine, particularly stick margarine, can contain 20% to 30% of trans fats. The American Heart Association now recommends soft margarine. Such margarine, so called trans-free margarine, which is formulated from either completely hydrogenated palm oil or palm oil fractions, has been introduced recently. This margarine, while free of trans fats, contain increased levels of saturated fats, the second most dangerous component of margarine.
Other compounds have been reported to reduce cholesterol levels in humans. For example, plant sterols, particularly beta-sitosterol, have been reported to have anticholesterolemic effects, and are believed to inhibit cholesterol absorption in the small intestine. Plant sterols are thought to displace cholesterol in bile salt micelles. Approximately half of the dietary cholesterol ingested is absorbed whereas less than 5% of beta-sitosterol is absorbed. When the plant sterols displace cholesterol of the bile salt micelles, the cholesterol is fecally excreted.
Plant sterols exist naturally in saturated and unsaturated forms, as free alcohols and as esters. The unsaturated forms dominate. It is known that natural sitosterols may be converted to sitostanols by hydrogenation, and it has been reported that stanols are more effective per unit weight than sterols in blocking cholesterol absorption and that stanols are not absorbed. Further, the amount of beta-sitosterol absorbed appears to be relatively constant even when doses administered vary by an order of magnitude. Both sterols and stanols have been used as relative markers of cholesterol absorption because of their unabsorbability. However, it seems clear that while sitostanol is completely unabsorbed, some sitosterol is.
Further, the addition of sitostanol to the diet reduces not only cholesterol absorption but also sitosterol and vitamin absorption. Some have characterized this as an advantage, but the fact that sitostanols block the normal absorption of micronutrients may be problematic.
The Lancet 1995; 345: 1529-1532, reported on the use of beta-sitosterol (20 milligrams per day) for the treatment of benign prostatic hyperplasia (BPH). This condition is a slow enlargement of the fibromuscular and epithelial structures within the prostate gland, eventually leading to obstructive urinary symptoms which are experienced to some extent by most men over the age of 50 years. Using sitostanols alone as an anti-cholesterolemic thus may increase the risk of BPH.
Other compounds that have been studied in connection with the treatment and prevention of diseases including arteriosclerosis and high cholesterol levels include tocotrienols, which are natural forms of vitamin E found in wheat germ, rice bran, oats and palm.
In vitro, the concentration-dependent impact of tocotrienols on cholesterol can be demonstrated to involve post-transcriptional down regulation of 3-hydoxy-3-methyl-glutaryl coenzyme A reductase (HMGCoA reductase) activity. This is the enzyme targeted by statins, the anti-cholesterolemic drug with annual sales of eight (8) billion dollars in the U.S. alone. Statins act directly, blocking HMGCoA reductase. However, statins also sometimes cause liver dysfunction.
Unfortunately, many patients taking statins or tocotrienols respond to the decreased rate of cholesterol synthesis by a compensatory increase in the rate at which dietary cholesterol is absorbed from food. A recent study reports that 80% of patients taking statins as a monotherapy failed to reach treatment goals. With respect to statins, increasing the dosage to the levels frequently required to overcome compensatory increase in cholesterol absorption, produces an 11-fold increase in the incidence of liver complications as noted above. Because of the risk of liver complications, statins must be taken under a doctor's supervision. Similarly, while tocotrienols have shown promise in vitro, the results of clinical trials have been equivocal. Qureshi, Am. J Clin. Nutr. 53: Suppl. 4: 1021S-1026S, (April 1991 ) reported significant improvements in lipid parameters amongst "responders" in a short study, but three subsequent studies of free living patients supplemented with the same material (palm-derived tocotrienol-rich fraction, i.e., palm-derived TRF) failed to confirm his results. See Antila, et al, Helsinki Antioxidant Symposium, 1991 Wahlquist, M., et al, Nutrition Research 12: Suppl. 1: S181-S201 (1992); Tomeo, A., et al., Lipids 30: 1179-1183, 1995] In response, Qureshi has suggested Qureshi, A., et al, Lipids 30 (12): 1171-1177, (1995) that d-tocopherol inhibits the anticholesterolemic effect of tocotrienols. The results of clinical trials with oils according to the present invention do not support this conclusion, but rather show that synergy with other non-saponifiable components is required to effect blood lipid modulation.
A margarine recently introduced in Finland, Benecol, that contains hydrogenated plant sterols extracted from pulp and paper waste, has been found to achieve a 10-15% reduction in cholesterol levels in patients substituting Benecol margarine for standard margarine in their diets. This reduction corresponds to a twenty to thirty percent decrease in cardiovascular risk. However, Benecol suffers from the disadvantage that the plant sterol extracts require regulatory approval in the United States and other countries as a new food additive.
Toxic forms of oxygen have been associated with many chronic, debilitating diseases. These include cardiovascular, neoplastic, arthritic, age related macular degenerative and progeria, among others. As tissue levels of these toxic forms of oxygen rise, tissue levels of protective antioxidants, such as antioxidants of the vitamin E family, decline. These risk factors have been confirmed in the case of cardiovascular disease by Gey, who showed that as blood vitamin E values decrease in a population, the incidence of ischemic heart disease rises. To assess the blood levels of peroxides, many researchers have measured adducts of thiobarbituric acid (a.k.a TBARS, thiobarbituric acid reactive substances, also called malonaidehyde modified material), or peroxides. Holvoet, Collen and van de Werf recently documented the relation of malonaldehydemodified LDL as a marker of acute coronary syndromes. These scientists showed that malonaldehyde (TBARS) type pollution in the blood indicates endothelial injury and plaque instability, and more accurately indicates acute coronary syndromes than other commonly used indices, such as troponin 1. In an intervention study of patients who had had at least one stroke who were supplemented daily with Redeem, their serum levels of TBARS material decreased significantly from pre-study values. See: Tomeo, A. C., el al. Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis. Lipids 30: 1179-1183, 1995; Watkins, T. R. et al. Hypocholesterolemic and antioxidant effects of rice bran oil non-saponifiables in hypercholesterolemic subjects. Environ. Nutr. Interactions, 3: (2) 1-8, 1999]. Further, their serum vitamin E levels nearly doubled over pre-study values. This same group of researchers of the Jordan Heart Research Foundation had previously documented the same relation in the laboratory rat model. See: Watkins, T. R., et al .gamma.-tocotrienol as a hypocholesterolemic and antioxidant agent in rats fed atherogenic diets. Lipids, 28: 1113-1118, 1993].
Accordingly, there is a need for an edible oil that is trans-free, low in saturated fats and suitable for use in the manufacture of margarine. Preferably, the edible oil does not require additives that must be chemically processed (e.g., hydrogenated).
There is also a need for an edible oil product that is a safe, effective alternative to known oil products and that can be made available over-the-counter (OTC) or incorporated into staple foods.
Furthermore, there is a need for a new intervention strategy against cardiovascular disease, one which recognizes the difficulty patients have in changing life-long bad eating habits and which, unlike cardiovascular drugs, is safe enough to be taken without direct medical supervision.